The proposed research program is focused on the molecular mechanisms that regulate vectorial growth of the neurite, especially, the local control of plasmalemmal expansion and cytoskeletal dynamics at the growth cone. This laboratory has demonstrated recently that plasmalemmal expansion at the growth cone is a regulated phenomenon and has discovered a putative, novel signalling cascade that may participate in its control. The cascade involves cleavage of phosphatidylinositol bisphosphate by phospholipase A2, generating arachidonic acid and lysopolyphosphoinositide. Activation of phospholipase A2 and the functions of its products will be analyzed using growth cones isolated from fetal rat brain (GCPs) as the primary experimental system and a series of cell biological and biochemical techniques. The major aims are: (i) to establish the link of PLA2 with a receptor and isolate its ligand; (ii) to study the possible functional role(s) of lysopolyphosphoinositide as a fusogen in membrane expansion and as a ligand for actin-binding or other intracellular growth cone proteins; (iii) to investigate the cones and as a membrane fusogen; (iv) to correlate plasmalemmal expansion and growth cone motility viewed in intact growth cones in culture with the biochemical data generated in cell-free systems by the other aims. These studies will lead to new insights into the mechanisms that regulate locally growth cone advancement and behavior and are expected to result in the isolation of factor(s) that modify these functions.